Microarray analysis unmasked two siblings with pure hereditary spastic paraplegia shared a run of

Microarray analysis unmasked two siblings with pure hereditary spastic paraplegia shared a run of homozygosity region onchromosome 3q28–q29

JournaloftheNeurologicalSciences359(2015)351–355

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JournaloftheNeurologicalSciences

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Microarrayanalysisunmaskedtwosiblingswithpurehereditaryspasticparaplegiasharedarunofhomozygosityregiononchromosome3q28–q29

WenqianYua,1,XiangdongYoub,1,DongWanga,KaiDonga,JingSuc,ChuanfenLic,JinxiuLiua,QianqianZhanga,FengYoua,XiangrongWanga,JingHuanga,BinQiaoa, ,2,WenyuanDuana, ,2

abc

InstituteofCardiovascularDisease,GeneralHospitalofJinanMilitaryRegion,8LashanRoad,Jinan250022,China

DivisionofQualityManagement,ShandongCenterforDiseaseControlandPrevention,16992JingshiRoad,Jinan250014,ChinaDepartmentofNeurology,GeneralHospitalofJinanMilitaryRegion,25ShifanRoad,Jinan250031,China

articleinfoabstract

Hereditaryspasticparaplegia(HSP)isaclinicalandgeneticheterogeneitygroupofneurodegenerativedisorderswhichischaracterizedbyprogressiveweaknessandspasticityofthelowerlimbs.Morethan70genetictypesofHSPhavebeendescribedsofar.HerewedescribeaChinesenon-consanguineousfamilywithtwoaffectedsiblingsmanifestingearly-onsetautosomalrecessiveHSPinpureforms.Toidentifygenotypeandcharacterizephenotype,CytoScanHDarrayanalysiswasperformedonthetwosiblings.Arunofhomozygosity(ROH)sharedbythetwopatientswasdetectedonchromosome3q28–q29.TheROHregion,about7.7Mbonthechromosome3:190172058-197851260partiallyoverlappedwiththeROHregionofSPG14previouslyreported.Subsequently,microsatelliteanalysiscon rmedthisROHandwhole-exomesequencingwascarriedoutwhilenocausativemu-tationswerefoundintheexonsofknownHSPgenesand68candidategenesinthatregion.Inconclusion,ourdatasuggesttheROHinthisregionmayplayapivotalroleinSPG14pathogenesis.Thisisthe rstclinicaldescriptionofapureformspasticparaplegiainanon-consanguineousfamilyassociatedwiththeSPG14locus.

©2015ElsevierB.V.Allrightsreserved.

Articlehistory:

Received12January2015

Receivedinrevisedform21October2015Accepted27October2015

Availableonline4November2015Keywords:

HereditaryspasticparaplegiaMicroarray3q28–q29

RunofhomozygositySPG14

Autosomalrecessive

Neurodegenerativedisorder

1.Introduction

Hereditaryspasticparaplegia(HSP)isoneofthemostclinicallyandgeneticallyheterogeneousgroupsofinheritedneurodegenerativedisordersmainlycharacterizedbyslowlyprogressivelower-limbspas-ticitywhichworsensovertime.Theneuropathologic ndingistheresultofthelongmotoraxonsofthecorticospinal-tractdegeneration[1–3].Themodesofinheritanceincludeautosomaldominant(AD-HSP),autosomalrecessive(AR-HSP),X-linkedormitochondrialtrait[4,5].Clinically,HSPsareclassi edaspureandcomplicatedforms.ThecomplicatedHSPsarecombinedwithfurtherneurologicalandsystemicabnormalities,whereasthepureformsessentiallyexhibitedlowerlimbweaknessandspasticity.Todate,morethan70differentlocihavebeenmappedand55spasticparaplegiagenes(SPGs)wereidenti ed.ThecorrespondingproteinsofSPGsplaykeyrolesintheregulationofintracellularmembranetraf cking,endoplasmicreticulummembrane

shaping,DNArepair,autophagy,mitochondrialfunction,lipidmetabo-lismandmyelinformation[6–8].

SPG14isanautosomalrecessiveformofHSPwhichhasbeenmappedtoacandidatediseaselocusonchromosome3q27–q28be-tweenmarkersD3S1580(chr3:188542793–188543136)andD3S3669(chr3:192501965–192502314)[9].Bynowonlyasingleconsanguine-ousItalianfamilywiththreeaffectedsubjectspresentingacomplexphenotypeincludingmildmentalretardationandmilddistalmotorneuropathyhasbeendescribed.

Herein,wereportedtwosiblingsborninanon-consanguineousChinesefamilywithspasticparaplegia.TheclinicalmanifestationsofourpatientspresentapureformofHSP.SNPmicroarraycon rmedanROHonchromosome3q28–q29ofthetwoaffectedsiblingsthatpartiallycoincidedwiththeregionofSPG14inthepreviousreport.2.Patientsandmethods2.1.Patients

Correspondingauthors.

E-mailaddresses:cijnmd@(B.Qiao),dwy2115@(W.Duan).1

The rsttwoauthorscontributedequallytothiswork.2

Thetwocorrespondingauthorscontributedequallytothis

work.

Thepresentstudyinvolvedtwosiblingsfromafamilywithpurespasticparaplegia.ThefamilypedigreeisshowninFig.1.Theirparentsarenon-consanguineousmarriage,andtheirfatherdiedofcirrhosis

/10.1016/j.jns.2015.10.057

0022-510X/©2015ElsevierB.V.Allrights

reserved.

Microarray analysis unmasked two siblings with pure hereditary spastic paraplegia shared a run of homozygosity region onchromosome 3q28–q29

352W.Yuetal./JournaloftheNeurologicalSciences359(2015)351–355

Fig.1.PedigreeoftheAR-HSPfamily.Thehaplotypesarecomposedof fteenmicrosatellitemarkersfromchromosome3q28–3q29.Longgreenbarsindicatethehomozygosityregionthatissharedbythetwopatients(betweenD3S1288toD3S3707).

7yearsago.Twoaffected(III-1andIII-2)andsixunaffectedmembers(II-2–4andII-6–8)wereexaminedbytwoexperiencedneurologists(Dr.Q-LSongandDr.JSu).Additionally,theaffectedindividualstooktheexaminationofmagneticresonanceimaging(MRI)andelectroen-cephalogram(EEG)analysis.

2.3.Exomesequencing

Paired-endsequencingwasperformedonIlluminaGAIIx/HiSeq2000instruments(Illumina,SanDiego,CA,USA)availableatShanghaiBiotechnologyCo.,Ltd.ExoncapturewasconductedusingAgilentSureSelectTechnology(Agilent,SantaClara,CA,USA).Forsequencealignment,variantcallingandannotation,thesequencesweremappedtotheirlocationwiththehumangenomereferencesequence(hg19build)usingaBurrows-WheelerAligner.Localrealignmentofthepotentialinsertion/deletionsiteswascarriedoutwithaGenomeanalysistool(GATK).SNPandindelvariantswereperformedagainstreferencedbSNP138.Allvariantswereannotatedwithreferencetocon-sensuscodingsequences(CCDS)(NCBIrelease20090902)andRefSeq(UCSCdumped20101004).ThenovelvariantswerecheckedwiththeIntegrativeGenomicsViewer(IGV),andthenfurtherinvestigatedinthefamilyandnormalChinesepopulation.3.Results3.1.Clinicaldata

ThepatientsaretwosiblingsfromaHanChinesefamily.Theeldersister(III-1)iscurrently18yearsold.Shewasbornattermwithanuneventfuldelivery.Sheexperiencedprogressiveweaknessofthelegsandtumbledseveraltimessincenine.Overthenextfewyears,gaitim-pairmentprogressedcontinuously;footdropandfootinversionwerepresentinherrightside.Atthetimeofadmissiontoourhospital,shewasbedriddenwithverylittlemobilityinherlegs.Theyoungerbrother(III-2)iscurrentlytenyearsold.Hewasnoticedslowlyprogressiveweaknessoflegsandgaitdisturbanceat7yearsold.Withthe

passage

2.2.Homozygositymapping

TotalgenomicDNAofthetwosiblingsandtheirmotherwereisolat-edandpuri edfromperipheralbloodusingtheQIAampDNAbloodminikit(Qiagen,Valencia,CA,USA).Then,theDNAsampleswereana-lyzedbyCytoScanHDarraysaccordingtothemanufacturer’sprotocol(Affymetrix,SantaClara,CA,USA).Brie y,250ngDNAwasdigestedwithNspIandligatedtoadaptersforsubsequentPCRampli cation.Theampli cationproductswerepuri edusingpuri cationbeads,fragmented,labeled,andhybridizedfor16–18hintheGeneChipHybridizationOven,ThearrayswerethenwashedwithaGeneChipFluidicsStation450,andscannedwithaGeneChipScanner30007G(Affymetrix).CopynumberandROHanalysiswereperformedusingtheAffymetrixChromosomeAnalysisSuitesoftware.

Fifteenmicrosatellitemarkerson3q28–q29includedD3S1580,D3S3530,D3S1294,D3S1288,D3S2747,D3S3043,D3S1601,D3S3663,D3S3669,D3S1523,D3S2305,D3S1305,D3S1272,D3S3707andD3S3550,nineofwhichwereconsistentwithG.Vazzaetal.[9]previ-ouslyreported.GenomicDNAoftheprobands,theirmotheranduncleswereextractedandusedforampli cations.FragmentswereanalyzedusinganABIPrism3730GeneticAnalyzer(AppliedBiosystems,ForsterCity,CA,USA)withthedenaturingPOP7polymer.ElectropherogramswereanalyzedusingGeneMappersoftware.

Microarray analysis unmasked two siblings with pure hereditary spastic paraplegia shared a run of homozygosity region onchromosome 3q28–q29

W.Yuetal./JournaloftheNeurologicalSciences359(2015)351–355353

oftime,heshowedslurredspeechandmildfootdrop.Hecanwalkwiththehelpofwalkingaidswhenarrivedatourhospital.Neurologicexam-inationofthetwopatientsrevealedweaknessandspasticityinthelowerlimbswithpositivepyramidaltractsigns(hypertonicityofthelowerlimbs,markedbilateralankleclonusandbilateralBabinskisigns),pescavusandplantarhypermyotonia.Noneofthemdisplayedabnormalitiesonelectroencephalography(EEG).Theirbrainswerealsonormalbasedonmagnetic-resonanceimaging(MRI).Atthetimeofrecentvisit,theeldersisterwascon nedtobedwithmalnutritionandamyotrophy,whichmightbepartiallyascribedtodisuseatrophy.Nystagmuswasobservedinbothpatients.ThedetailedinformationissummarizedinTable1.Bothofthemwereclassi edaspureHSPbytwoexperiencedneurologists(Dr.Q-LSongandDr.JSu).ExceptforIII-1andIII-2,otherindividualsfromthisfamilyarenormalinclinicalmanifestationsandauxiliaryexaminations.

3.3.Mutationanalysis

Whole-exomesequencingwasperformedontheIII-1,III-2andII-6.Theresultscovered93%ofthetargetregionwiththemedianreaddepth(102×,100×and81×),26,033SNPsand258indelswereidenti ed.SinceHSPwasassumedtobeaveryrareconditionandnoclinicalsig-ni cantmutationinknownHSPgeneswasdetected,weexcludedheterozygouschanges,changesnotsharedbytheaffectedsiblingsandhomozygouschangesconsistentwiththeirmother.Tenhomozygousvariationswithafrequencyofb1%indbSNP138wereidenti ed,twoofwhichwerein5′UTRregionsandonewasintheintronicregion.Thefrequencyofthesethreevariantsrangedfrom0.1to0.4%referencedinthedbSNP138(rs185421189,rs147536472andrs191327348).NoneofthemwaslikelypathogenicsincetheydidnotaffectsplicesitesthroughpredictionbytheHumanSplicingFinder(HSF).Thesevenre-mainingvariantswerelocatedinexoncodingsequences,threeofthemweremissensevariantsinC3orf43,CRLF1andKIR3DL1genespreviouslyreportedinthedbSNP138,HapMap,and1,000GenomesDatabase(rs118152136,rs117193413andrs150084719respectively),theywerepredictedasbenignbySIFTandPolyphen2predictionpro-grams.Theremainingweresynonymousmutations,twoofwhichhadfrequency0.5%indbSNP138(rs35480846,rs139525246),andwerepredictedtobenon-pathologicbyHSF.Theothertwonovelsynony-mousvariant,oneofwhichlocatedatthe rstexonoftheMUC4gene(c.G10605C),theotherwasavariantintheFBXO45genec.33CNT.However,theywerebothpredictednottoaffectadjacentsplicesitesoractivatecrypticsplicesites.

Furthermore,Sangersequencingwasperformedontheexonsandpromoterregionsofcandidateeightgenes(IL1RAP,GEMC1,SNAR-I,OSTN,UTS2D,CCDC50,PYDC2andFGF12).27variantswereidenti ed,ninelocatedinexonoruntranslatedregions(UTR)regions.TheSangersequencingresultsoftheninevariantswereconsistentwiththoseofexomesequencing(SupplementTable2).Asthephenotypeofourpa-tientsappearedtobeanautosomalrecessivemodel,wefocusedonho-mozygousmutationsintheaffectedindividualsthatwereheterozygousintheirmother.Fourhomozygousvariationswithafrequencyofb1%indbSNP138wereidenti ed(markedwithboldfont).However,noneof

3.2.Theresultsofhomozygositymapping

Thecytogeneticsrevealednormalkaryotypes(46,XXand46,XY)inthetwosiblingswithnoabnormalitydetected.Microarrayanalysisofthetwosiblingsandtheirmotherdidn'tidentifyanyclinicalsigni canceregionsofcopynumbervariation.Assmallerstretchesofhomozygosity(b3Mb)spreadthroughoutthegenomearecommoneveninoutbredpopulations[10],wesetasizethreshold(N3Mb).Thesegmentsbelow3Mbwerenotconsideredtobesigni cant.AnROHonthechro-mosome3q28–q29(Fig.2)wasdetectedinthetwosiblings,whichwasabout7.7Mbandcoveredthebasepairpositionsfrom190172058to197851260(hg19)including68genes.Moreover,thisregionpartiallyoverlappedwiththeSPG14locusandtheoverlappingregionincluded8genes(IL1RAP,GEMC1,SNAR-I,OSTN,UTS2D,CCDC50,PYDC2andFGF12)(SupplementTable1).

Tocon rmthehomozygositysharedbythetwosiblings,wegenotypedpolymorphismsusing15single-nucleotidemicrosatellitemarkersinfamilymembers.Theresultscon rmedtheROHregionofthetwosiblingsonthetelomereofchromosome3betweenmarkersD3S1288andD3S3707(Fig.1).

Table1

Clinicalfeaturesoffamilieswith3q28–q29ROH

PresentfamilyIII-1

ROHregionEthnicitySex

Ageatexamination,yAgeatonset,ySymptomatonsetUpperlimbsSpasticityWeaknessHyperre exia

LowerlimbsSpasticityAnkleclonusAmyotrophyWeaknessHyperre exiaDystoniaBabinskisignPescavus

ExtensorplantarresponsesWalkingabilityCognitivedeclineNystagmusEEGMRI

a

G.Vazzaetal

III-2

Chinese-HanMale107

Weaknessoflowerlimb

II-2

II-6

II-8ItalianFemale52

Spasticgait

Chr3:190172058–197851260Chinese-HanFemale189

Weaknessoflowerlimb;spasticgaitChr3:188542793–192502314ItalianItalianMaleFemale6254

Average30

SpasticgaitSpasticgaitNRaNRNR

––––––NRNRNRNRNRNR

+++++++++

Walker–

+(mild)NormalNormal++–++++++

Walker–

+(mild)NormalNormal+NRNR+++NR++

Unaided+NR

NormalNormal+NRNR+++NR++

Unaided+NR

NormalNR+NRNR+++NR++

Unaided+NR

NormalNR

NRindicates“NotReported”.

Microarray analysis unmasked two siblings with pure hereditary spastic paraplegia shared a run of homozygosity region onchromosome 3q28–q29

354W.Yuetal./JournaloftheNeurologicalSciences359(2015)351–355

Fig.2.(A)Thesiblingswithacompletesimilarregionofrunofhomozygosity(ROH)onchromosome3whichisabsentintheirmother.(B)SNPdatadisplayedinChASshowingtheROHfrom3q28.3to3qter.

thevariantswerelikelypathogenicsincetheywerenotinclinedtoaf-fectsplicesitesaccordingtothedataofHSF.

4.Discussion

Inthisresearch,wedescribetwopatientsfromanon-consanguineousfamilywithpurespasticparaplegia.Afterexcludingthecontributionofcopynumbervariationincludingdeletionsandduplications,anROHonchromosome3q28–q29wasidenti ed.Theregionwasabout7.7Mbonthechromosome3:190172058–197851260including68geneswhichpartiallycoincidedwithSPG14region.Theoverlappingregionincluded8genes(IL1RAP,GEMC1,SNAR-I,OSTN,UTS2D,CCDC50,PYDC2andFGF12).Subsequently,theROHregionwascon rmedbymicrosatelliteanalysis.

Longcontiguousstretchesofhomozygositycanbeassociatedwithconsanguinityoruniparentaldisomy,bothofwhichincreasetheriskofautosomalrecessivediseases[11].TheconservativeclinicalsetathresholdsforROHbetween3and10Mb,whenasecondchromosomehadaROHN10Mb,indicatingidentitybydescentandconsideringex-clusionofpatientsfromuniparentaldisomy[12,13].OurpatientIII-1hasa7.7MbROHonthelongarmofchromosome3and11.4MbROHonthechromosome6p(SupplementFig.1),whichwaslikelytoindi-catehomozygositybyvirtueofparentaldescentfromacommonances-tor[14–16].

AR-HSPcausedbySPG14ischaracterizedbyprogressivespasticity,hyperre exia,andmildlower-limbhypertonicitywiththe30yearsaverageageofonset[9].Allaffectedmembersshowedneuropsycho-logicalimpairmentandbilateralpescavusandnonedisplayedabnor-malitiesonelectroencephalography[9].Thetwosiblingsinourstudyexperiencedonsetat9and7yearsold,respectively.Themainclinicalmanifestationsofthetwopatientswerespasticparaplegiaofthelowerlimbs,partiallyaccompaniedwithpescavus,amyotrophy,andmildnystagmus.AllofthesemanifestationsinourpatientsindicatedapureformofHSP.AlthoughitisnotpossibletoinferthatthesamegeneisresponsibleforSPG14andthediseaseinourfamily.Phenotypi-calvariabilitycausedbyalleleheterogeneityhasbeenobservedinmanydisordersincludingHSP[17–19].

TheexomesequencingresultsrevealedthattherewasnopathogenicmutationintheROHregionandotherchromosomes.Sangersequencingcon rmedtheexomesequencingresultoftheeightgenes(IL1RAP,GEMC1,SNAR-I,OSTN,UTS2D,CCDC50,PYDC2andFGF12)inROH,andnocausativemutationwasfoundinpromoterregionsofthosegenes.Sincethemicroarrayanalysisdetecteda7.7MbROHregiononchromo-some3q28–q29andsubsequentlycon rmedbymicrosatellitemarkers.WespeculatedthattheintervalofSPG14mightbelongerthanpreviousthoughtfromchromosome3:190172058tochromosome3:197851260.Therewere68genesintheROHregion,someofwhichseemtoberelat-edwithspasticparaplegia.PreviousstudiesshowedthatFGF12knockoutmicedisplaymuscleweaknessandFGF12-/-/FGF14-/-mice

represented

Microarray analysis unmasked two siblings with pure hereditary spastic paraplegia shared a run of homozygosity region onchromosome 3q28–q29

W.Yuetal./JournaloftheNeurologicalSciences359(2015)351–355355

severeataxiabehavior[20,21],andFGF12mightberelatedtoHSPinhuman;theubiquitinligaseF-boxprotein45(FBXO45)iscriticalforsyn-aptogenesis,synaptictransmissionandneuronalmigrationindevelop-ingcentralandperipheralneurons[22].RecentresearchsuggestedthatFBXO45mightbeacandidategeneforschizophreniaandcerebralpalsy[23,24].Therefore,furtheranalysisofnon-codingregions,intronicandmRNAexpressionofthegenesinthecriticalROHregionneedtobeconductedtoidentifythegenesresponsibleforSPG14.

Inconclusion,weidenti edthe rstpureformofHSPinaChinesenon-consanguineousfamilywitha7.7MbROHonchromosome3q28–q29whichpartiallyoverlappedthelocusofSPG14.TheseresultssuggestedthatthesharedROHregiondetectedinourpatientshelpedtocon rmthecandidateregionon3qterassociatedwithSPG14.

Supplementarydatatothisarticlecanbefoundonlineat/10.1016/j.jns.2015.10.057.Con ictofinterest

Theauthorsdeclarenocon ictsofinterest.Acknowledgments

Theauthorsaregratefultoallthepeoplewhoprovidedhelpforthisstudy.ThisworkwassupportedbythegrantsfromtheNationalBasicResearchProgramofChina,(2013CB945402,2013CB945403).References

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